Pharmaceuticals containing prostaglandin I2

ABSTRACT

Disclosed is a pharmaceutical having circulation ameliorating effect and antiulcer effect containing a prostaglandin I 2  analogue represented by the formula shown below or a non-toxic salt of its salt or a cyclodextrin inclusion compound thereof as the effective ingredient: ##STR1## wherein R 1  represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 4 to 7 carbon atoms or a phenyl group; A represents a pentyl group, a cyclopentyl group, a cyclohexyl group, a 1-methyl-3-hexynyl group, a 2-methyl-3-hexynyl group, a 1-methylhexyl group, a 2-phenethyl group, a 1,1-dimethylpentyl group, a 2-methylpentyl group, a 1-cyclohexylethyl group, a 2-methylhexyl group, a 1-methyl-3-pentynyl group or 1 2,6-dimethyl-5-heptenyl group; the double bond between the carbon atoms at 4- and 5-positions is E or Z or a mixture thereof, the asymmetric center in the substituent represented by A is R-configuration or S-configuration or a mixture thereof. 
     The pharmaceuticals containing, as an active ingredient, prostaglandin I 2  analogues of the present invention have potent platelet aggregation inhibiting effect, blood pressure depressing effect, vasodilative effect and antiulcer effect, and are also low in toxicity.

This application is a continuation of application Ser. No. 07/333,733,filed April 3, 1989, now abandoned which is a continuation ofapplication Ser. No. 07/206,943 filed June 13, 1988 now abandoned, whichis a continuation of application Ser. No. 07/099,779 filed Sept. 22,1987 now abandoned which is a continuation of application Ser. No.06/763,618 filed Aug. 8, 1985 now U.S. Pat. No. 4,699,921 issued Oct.13, 1987.

BACKGROUND OF THE INVENTION

This invention relates to prostaglandin I₂ analogues and uses thereoffor circulation ameliorating pharmaceuticals for blood flowamelioration, antithrombotic or antiulcer pharmaceuticals.

Prostaglandin I₂ (hereinafter written as PGI₂) has been known as anatural physiologically active substance and has the stucture shown bythe following formula: ##STR2## Its chemical name is(5Z,13E)-(9α,11α,15S)-6,9-epoxy-11, 15-dihydroxyprost-5,13-dienic acid.PGI₂ exists within the vascular walls and is the most potent inhibitorof platelet aggregation as well as being a powerful vasodilator [Nature,263, 663 (1976)].

PGI₂ exhibiting such properties is useful for prophylaxis and therapy ofcerebral thrombosis, myocardial infarction and acute stenocardia inducedby exasperation of platelet aggregation and further increase ofthrombotic tendency, expected to be appicable for prophylaxis andtherapy of arteriosclerotic diseases and desired to be developed as theso-called circulation ameliorating or antithrombotic pharmaceuticals.

Also, many prostaglandins containing PGI₂ are known to have gastricmucosa protective effect and blood flow increasing effect within gastricmucosa ['83 Inflammation Seminar "Prostaglandin" Pretext page 50(sponsored by Society of Inflammation of Japan)], and PGI₂ having sucheffects can be expected to be applicable for prophylaxis and therapy ofgastrointestinal ulcers, typically stomach ulcer.

However, PGI₂ is remarkably unstable and this has been an obstacleagainst practical application as pharmaceuticals.

In order to overcome such an obstacle, studies have been made aboutstable analogues in which the oxygen atom between the carbon atoms atthe 6- and 9-positions in PGI₂ is replaced with carbon atom. Thecarbacycline type compounds [Japanese Provisional Patent Publication No.130543/1979] of the chemical formula (III) as represented by OP-41483[Japanese Provisional Patent Publication No. 130543/1979] and9(0)-methano-Δ⁶ -PGI₁ of the chemical formula (IV) [Japanese ProvisionalPatent Publication No. 32426/1981] are all chemically stable PGI₂analogues. Also, 9(0)-methano-Δ⁶( 9α)-prostaglandin I₁ (isocarbacyclin[Tetrahedron Letters, 24, 3493 (1983)], chemical formula (V)) in whichthe 5-position double bond in 9(0)-methano-prostacyclin (carbacyclin) istransferred to the 6(9α) position is also chemically sufficiently stableand has been reported as a PGI₂ analogue having potent physiologicalproperties [Japanese Provisional Patent Publication No. 137445/1984].##STR3##

SUMMARY THE INVENTION

The present inventors have made extensive studies in order to provideprostaglandin I₂ analogues which are stable, substantially free fromdecomposition at room temperature and have excellent pharmacologicalproperties, and consequently created novel prostaglandin I₂ analoguesand found that said analogues have potent platelet aggregationinhibiting effect, hypotensive effect, vasodilative effect and antiulcereffect, and are also low in toxicity, to accomplish the presentinvention.

Thus, the present invention provides a pharmaceutical containing aprostaglandin I₂ analogue represented by the formula (I): ##STR4##wherein R¹ represents a hydrogen atom, an alkyl group having 1 to 12carbon atoms, a cycloalkyl group having 4 to 7 carbon atoms or a phenylgroup, A represents a pentyl group, a cyclopentyl group, a cyclohexylgroup, a 1-methyl-3-hexynyl group, a 2-methyl-3-hexynyl group, a1-methylhexyl group, a 2-phenethyl group, a 1,1-dimethylpentyl group, a2-methylpentyl group, a 1-cyclohexylethyl group, a 2-methylhexyl group,a 1-methyl-3-pentynyl group or a 2,6-dimethyl-5-heptenyl group, thedouble bond between the carbon atoms at 4- and 5-positions is E or Z ora mixture thereof, the asymmetric center in the substituent representedby A is R-configuration or S-configuration or a mixture thereof,

as the effective ingredient.

PREFERRED EMBODIMENTS OF THE INVENTION

The compound of the present invention was found to exhibit potentplatelet aggregation inhibiting effect, vasodilatory effect, hypotensiveeffect and antiulcer effect in animal experiments. Such plateletaggregation inhibiting effect and vasodilatory effect suggest that thepresent compound is an excellent blood flow ameliorating agent or anantithrombotic drug for prophylaxis or therapy against cerebralthrombosis, myocardial infarction, acute stenocardia, peripheralcirculation disorders, etc. caused by platelet aggregation exasperationor arteriosclerosis. Further, the hypotensive effect suggests that thepresent compound is an excellent antihypertensive for prophylaxis ortherapy against hypertensions. Moreover, the antiulcer effect suggeststhat the present compound is an excellent antiulcer drug for prophylaxisor therapy against gastrointestinal ulcers, typically stomach ulcer.

In the animal experiments, the compound of the present invention provedto be low in toxicity, and this fact suggests that it is an excellentpharmaceutical with high safety.

In the compounds of the present invention represented by the aboveformula [I], R¹ represents a hydrogen atom, an alkyl group having 1 to12 carbon atoms, a cycloalkyl group having 4 to 7 carbon atoms or aphenyl group. The alkyl group having 1 to 12 carbon atoms may includestraight or branched alkyl groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-amyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl and the like.The cycloalkyl group having 4 to 7 carbon atoms may be exemplified bycyclobutyl, 1-propylcyclobutyl, cyclopentyl, 2-pentylcyclopentyl,cyclohexyl, 3-ethylcyclohexyl, cycloheptyl and the like.

Specific examples of the prostaglandin I₂ analogues provided by thepresent invention may include 3-(4'carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound A) and its methyl ester (Compound A'),3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyltrans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound B) and itsmethyl ester (Compound B'),3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound C) and its methyl ester (Compound C'), 3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'methyl-trans-1'-decen-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound D) and its methyl ester(Compound D'), 3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclohexyl-trans-1'-propenyl)-7(R)-hydroxy(1S,5S) -cis-bicyclo[3.3.0]oct-2-ene (CompoundE) and its ethyl ester (Compound E'),3-(4'-carboxy-1'-butenyl)6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-nonen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound F) and its ethyl ester (Compound F'),3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(RS)-methyltrans-1'-nonen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound G) and itsethyl ester (Compound G'),3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-nonenyl)-7(R)-hydroxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound H) and its ethyl ester (Compound H'),3-(4'-carboxy-1'-butenyl)-6(S)(3'(S)-hydroxy-5'-phenyl-trans-1'-pentenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound I) and its ethyl ester (CompoundI'),3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-4',4'-dimethyl-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound J) and its ethyl ester (Compound J'),3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(RS)-methyltrans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound K) and itsethyl ester (Compound K'),3-(4'-butenyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)cyclohexyl-trans-1'-pentenyl)-7(R)-hydroxy-(1S,5S)-cisbicyclo [3.3.0]oct-2-ene (Compound L) and itsethyl ester (Compound L'),3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(RS)-methyl-trans-1'-nonenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]-oct-2-ene (Compound M) and its 5 ethyl ester(Compound M'), and further inclusion compounds of these compounds andcyclodextrin.

In application of the compounds of the present invention for clinicaluses as the blood flow ameliorator, antithrombotic, antihypertensive andantiulcer, the effective administration may be either oral orparenteral, and they can be administered at a dose of 0.1 μg to 100 mgper one administration, desirably at a daily dose of 1 μg to 1 mg in oneor several divided doses. However, the accurate dosage depends on theage, body weight, severity of disease of the patient, the administrationroute and the number of administrations.

The solid preparations for oral administration may include tablets,pills, powders and granules. In such solid preparations, one or moreactive substances may be mixed with at least one inert diluent such ashalf-digestable starch, potato starch, alginic acid, mannitol orsucrose. The preparation may also contain additives other than diluents,for example, lubricants such as magnesium stearate, according to aconventional manner. The liquid preparations for oral administraton maycontain parmaceutically acceptable emulsions, solutions, suspensions orelexirs, and may also contain, in addition to inert diluents in general,auxiliary agents such as wetting agents, suspension aids, sweetners,flavors, aromatics or preservatives. As other preparations for oraladministration, there may also be included capsules of absorbablematerials such as gelatin containing at least one active substancetogether with or without diluents or excipients.

As the solid preparation for rectal administration, there may beincluded suppositories comprising one or more active substance and atleast one inert base such as cacao butter, macrogol, Witepsol, and whichcan be treated according to the method known per se. Further, as thepreparation for topical application, ointments, etc. may be employed.

The product for parenteral administration contains sterile aqueous ornon-aqueous solvents, suspending agents or emulsifiers. Non-aqueoussolvents or suspending agents may include propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, injectable organic acid esterssuch as ethyl oleate. Such preparations can also contain auxiliaryagents such as preservatives, wetting agents, emulsifiers anddispersants. They can be sterilized by filtration through a bacteriaretaining filter, formulation with a sterilizer or by irradiation. It isalso possible to prepare sterile solid preparations which are to bedissolved in a sterile solvent for injection immediately before use.

As for acute toxicity of the compounds of the present invention, inintraveneous administration to mouse, each LD₅₀ value of the compoundsof the present invention was found to be 1000 μg/kg-animal weight orhigher, and no change in state was observed at all at levels ofadministration of 1000 μg/kg-animal weight or lower.

The compounds of the present invention represented by the formula (I)can be produced according to, for example, the route shown below by useof the known compound (VI) as disclosed together with its syntheticmethod in [Collected Gists of Lectures, the 45th Symposium on thesynthetic organic chemistry (sponsored by The Society of SyntheticOrganic Chemistry, JAPAN)]. ##STR5##

[wherein R¹ represents an alkyl group having 1 to 12 carbon atoms, acycloaklyl group having 4 to 7 carbon atoms or a phenyl group; R²represents a protective group for a hydroxy group which is eliminableunder acidic conditions; and A is the same as defined above].

The compound (VII) can be prepared by allowing the compound (VI) toreact with the Wittig reagent obtained by the treatment of R³ ₃ P⁺ CH₂CH₂ CH₂ CO₂ R^(1') X⁻ [wherein R^(1') is the same as defined above; R³is an alkyl group having 1 to 4 carbon atoms or a phenyl group; X³¹ is ahalogen atom such as chlorine, bromine, etc.] with a base. As the base,sodium hydride, potassium hydride or potassium tert-butoxide maypreferably be employed. The amount of the Wittig reagent may be 1 to 10equivalents, preferably 1 to 5 equivalents, relative to the startingcompound. The reaction solvent may preferably be dimethyl sulfoxide orethers such as tetrahydrofuran, dimethoxyethane, etc. The reactiontemperature may be -78° C. to 50° C., preferably -20° C. to 30° C.

The compound (VIII) can be obtained by treating the compound (VII) with1 to 10 equivalents, preferably 1 to 3 equivalents of a fluorinecompound such as n-butylammonium fluoride or cesium fluoride. Thereaction may be carried out in an ether such as tetrahydrofuran, ethylether, etc. at a temperature of 0° to 30° C. for about 10 minutes to 3days.

The compound (IX) can be obtained by oxidizing the hydroxymethyl groupin the compound (VIII) to convert it to an aldehyde, and then allowingthe aldehyde to react with the Wittig reagent obtained by the treatmentof (R⁴ O)₂ P(O)CH₂ C(O)-A [wherein A is the same as defined above, R⁴ isan alkyl group having 1 to 3 carbon atoms]with a base. In oxidation ofthe hydroxymethyl group, it is preferred to employ the oxidation methodin which a system of amine/pyridine-sulfur trioxide complex/dimethylsulfoxide for oxidizing a primary alcohol to aldehyde is employed. Thereaction is carried out generally at 10° C. to 40° C. for about 1 minuteto 2 hours. The amount of the oxidizing agent used may preferably be inan excess, namely about 2 to 100 equivalents relative to the startingcompound (VIII). The aldehyde thus obtained should preferably besubjected as such without purification to the subsequent Wittigreaction. The base to be used in the Wittig reaction should preferablybe sodium hydride, potassium hydride or potassium tert-butoxide. Theamount of the reagent employed may be 1 to 10 equivalents, preferably 1to 5 equivalents, relative to the aldehyde. The reaction solvent maypreferably be an ether such as tetrahyrofuran, dimethoxyethane, etc.,and the reaction may be carried out at a temperature from -20° C. to 50°C. for about 5 minutes to 24 hours. These compounds (VII) to (IX) can bepurified according to conventional purification means such as columnchromatography, thin layer chromatography, liquid chromatography, etc.

The compound (X) can be obtained by reduction of the compound (IX). Asthe reducing agent, those which can not reduce COOR^(1') are preferred.For example, there may be included sodium borohydride, zinc borohydride,diphenyl tin hydride, lithium trialkylborohydride such as lithiumtri-sec-butylborohydride, di-isobutylaluminum hydride modified with2,6-di-tert-butyl-4-methylphenol, or lithium aluminumhydride modifiedwith 1,1'-bi-2-naphthol and a lower alcohol such as ethanol and so on.The reaction solvent may include lower alcohols such as methanol,ethanol and the like, ethers such as diethyl ether, tetrahydrofuran anddioxane, or aromatic hydrocarbons such as benzene and toluene. Theamount of the reducing agent used may preferably be 0.5 to 30equivalents, particularly 1 to 10 equivalents, relative to the startingcompound, the α,β-unsaturated compound. The reaction temperature may be-150° C. to 80° C., preferably -100° C. to 30° C. The reaction mixturethus obtained may be treated according to the post-treatments as usual.For example, the reaction mixture may be poured into dil. hydrochloricacid, dil. sulfuric acid or an aqueous saturated ammonium chloridesolution, extracted with an organic solvent poorly soluble in water suchas hexane, pentane, petroleum ether, ethyl ether, benzene or toluene,the combined extracts are washed with an aqueous sodium chloridesolution, dried over a drying agent such as anhydrous sodium sulfate,anhydrous magnesium sulfate, anhydrous potassium carbonate, etc., andthe organic solvent is evaporated to give a crude product. The crudeproduct can be purified according to purification means such as columnchromatography, thin layer chromatography, liquid chromatography, etc.,if desired. The product thus obtained may further be subjected to thedeprotection reaction, separation of diastereomers, hydrolysis reactionand salt forming reaction, if necessary.

Removal of the protective group on hydroxyl group may be practicedpreferably with the use of acetic acid, pyridinium salt ofp-toluenesulfonic acid or a cation exchange resin as the catalyst in asolvent such as water, tetrahydrofuran, ethyl ether, dioxane, acetone,acetonitrile, etc. The reaction may be carried out generally at -78° C.to 80° C. for about 10 minutes to 3 days. The product thus obtained maybe further subjected to separation of diastereomers based on the15-position hydroxyl group formed by the reduction reaction bypurification according to the purification means such as columnchromatography, thin layer chromatography, liquid chromatography, etc.

The hydrolysis reaction of the carbdxylic acid ester may be conducted inwater, methanol or ethanol alone or a mixture thereof containing causticsoda or caustic potash at a temperature range from -10° C. to 100° C.for one minute to 24 hours, or alternatively by use of an enzyme such aslipase in water or a solution containing water at a temperature rangefrom -10° C. to 60° C. for one minute to 24 hours. The product afterhydrolysis can be purified according to the same purification means asmentioned above

The present invention is described in more detail by referring to thefollowing Examples.

EXAMPLE 1 ##STR6##

(a)3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxotrans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cisbicyclo[3.3.0]oct-2-ene (73 mg, 0.16 mmol) was dissolved in methanol (2.6 ml).To the solution was added sodium borohydride (6 mg, 0.16 mmol) at -25°C. and the mixture was stirred at -25° C. for 40 minutes. After thereaction was stopped with addition of acetone, a saturated aqueousammonium chloride solution was added thereto. Methanol was distilled outand then the residual aqueous layer was extracted with ether. Theextract was washed with a saturated aqueous saline solution andthereafter dried with anhydrous magnesium sulfate. The solvent wasdistilled out and the residue was purified through silica gel columnchromatography to obtain 3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-trans-1'-octenyl)7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(74 mg, Yield: 100%) as a substantially colorless oily product.

IR (neat): 3470, 1745 cm⁻¹.

NMR δ(CDCl₃): 6.28 (d, J=16Hz, 1/3H, trans), 6.00 (d, J=11Hz, 2/3H,cis), 5.10-5.75 (m, 4H), 4.67 (1H, m), 3.70 (s, 3H).

Mass m/z: 446, 230.

(b)3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S) -cis-bicyclo[3.3.0]oct-2-ene (446 mg,1 mmol) was dissolved in THF (0.26 ml). To the solution was added a 65%aqueous acetic acid solution (2.6 ml) and the mixture was stirred at 50°C. for 2 hours. The reaction mixture was poured into a cooled saturatedaqueous sodium hydrogencarbonate solution and extracted with ethylacetate. The organic layer was washed with a saturated aqueous salinesolution and dried with anhydrous magnesium sulfate. The solvent wasdistilled out and the residue was purified through silica gel columnchromatography to obtain3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound A') (214 mg, Yield: 59%) as a colorless oilyproduct.

IR (neat): 3400, 1742 cm⁻¹.

NMR δ(CDCl₃): 6.30 (d, J=15Hz, 1/3H, trans), 6.02 (d, J=11Hz, 2/3H,cis), 5.00-5.70 (m, 4H), 4.10 (m, 1H), 3.70 (s, 3H), 3.02 (m, 1H).

Mass m/z: 362, 344.

[α]_(D) ²⁰ =-35° (c=0.466, MeOH).

EXAMPLE 2 ##STR7##

(a) The same reaction procedures were carried out as in Example 1-(a)except that 3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(130 mg, 0.29 mmol) was employed as a starting material to obtain3-(4'-methoxycarbonyl-1'-butenyl)6(S)-(3'(RS)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(131 mg, Yield: 100%) as a colorless oily product.

IR (neat): 3500, 1742 cm⁻¹.

NMR δ(CDCl₃): 6.28 (d, J=16Hz, 1/3H, trans), 6.00 (d, J=11Hz, 2/3H,cis), 5.10-5.80 (m, 4H), 4.70 (m, 1H), 3.70 (s, 3H).

Mass m/z: 444, 342, 298, 220.

(b) The same reaction procedures were carried out as in Example 1-(b)except that3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-3-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(444 mg, 1 mmol) was employed as a starting material to obtain3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound B') (198 mg, Yield: 55%) as a colorless oily product.

IR (neat): 3400, 1740 cm⁻¹.

NMR δ(CDCl₃): 6.22 (d, J=15Hz, 1/3H, trans), 5.95 (d, J=11Hz, 2/3H,cis), 5.17-5.75 (m, 4H), 3.65 (s, 3H), 3.40-4.00 (m, 2H).

Mass m/z: 360, 342.

[α]_(D) ²⁰ =-30° (c=1.16, MeOH).

EXAMPLE 3 ##STR8##

(a) 3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)(3'-oxo-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (450 mg, 0.99 mmol) was dissolved inmethanol (10 ml). To the solution was added an excess amount of sodiumborohydride at -25° C. and the mixture was stirred at -25° C. for 1hour. After the reaction was stopped with addition of acetone, asaturated aqueous ammonium chloride solution was added thereto. Methanolwas distilled out and then the residual aqueous layer was extracted withether. The extract was washed with a saturated aqueous saline solutionand thereafter dried with anhydrous magnesium sulfate. The solvent wasdistilled out and the residue was purified through silica gel columnchromatography to obtain3-(4'-methoxy-carbonyl-1'-butenyl)-6(S)-(3'(RS)hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (377 mg, Yield: 84%) as a substantiallycolorless oily product.

IR (neat): 3500, 1745 cm⁻¹.

NMR δ(CDCl₃): 6.30, 6.02 (each d, J=16, 12Hz, 1H), 5.20 -5.80 (m, 4H),4.60 (m, 1H), 3,71 (s, 3H), 1.69 (t, J=2Hz, 3H), 1.00 (m, 3H).

Mass m/z: 372, 354, 85.

(b)3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (350 mg, 0.77 mmol) was dissolved in THF(0.6 μl). To the solution was added a 65% aqueous acetic acid solution(6 μl) and the mixture was stirred at 50° C. for 2 hours. The reactionmixture was poured into a cooled saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous saline solution and dried withanhydrous magnesium sulfate. The solvent was distilled out and theresidue was purified through silica gel column chromatography to obtain3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound C') (143 mg, Yield: 50%) as a colorless oily product.

IR (neat): 3400, 1740 cm⁻¹.

NMR δ(CDCl₃): 6.25, 6.00 (each d, J=16, 12 Hz, 1H), 5.00 -5.70 (m, 3H),3.68 (s, 3H), 1.78 (t, J=2Hz, 3H), 0.98 (m, 3H).

Mass m/z: 372, 354, 336.

[α]_(D) ²⁰ =-16° (c=1.86, MeOH).

EXAMPLE 4 ##STR9##

(a) The same reaction procedures were carried out as in Example 3-(a)except that3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-5'(R)-methyl-9'-methyl-trans-1'-decen-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(490 mg, 0.98 mmol) was employed as a starting material to obtain3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-5'(R)-methyl-9'-methyltrans-1'-decen-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(492 mg, Yield: 100%) as a substantially colorless oily product.

IR (neat): 3500, 1745 cm⁻¹.

NMR δ(CDCl₃): 6.26, 6.00 (each d, J=15, 11Hz, 1H), 5.00 -5.62 (m, 5H),4.68 (m, 1H), 3.69 (s, 3H), 1.68 (s, 3H), 1.58 (s, 3H), 0.90 (d, J=6Hz,3H).

Mass m/z: 500, 482, 416, 85.

(b) The same reaction procedures were carried out as in Example3-(1)-(b) except that3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-5'(R)-methyl-9'-methyltrans-1'-decen-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo-[3.3.0]oct-2-ene(350 mg, 0.70 mmol) was employed as a starting material to obtain3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decen-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound D') (126 mg, Yield: 43%) as a substantially colorless oilyproduct.

IR (neat): 3400, 1740 cm⁻¹.

NMR δ(CDCl₃): 6.25, 6.00 (each d, J=15, 12Hz, 1H), 5.10 -5.80 (m, 5H),3.70 (s, 3H), 1.70 (s, 3H), 1.62 (s, 3H), 0.95 (d, J=6Hz, 3H).

Mass m/z: 416, 398, 380

[α]_(D) ²⁰ =-31 ° (c=2.29, MeOH).

EXAMPLE 5 ##STR10##

3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-1'-trans-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(15 mg, 0.04 mmol) was dissolved in methanol (0.3 ml). To the solutionwas added a 10% aqueous sodium hydroxide solution at 0° C. Afterstirring at 0° C. for 16 hours, the mixture was neutralized with a 10%aqueous hydrochloric acid solution while cooling. Under reducedpressure, methanol was distilled out and, after pH was adjusted to 3-4,the resultant mixture was extracted with ethyl acetate. The extract wasdried with anhydrous magnesium sulfate and then the solvent wasdistilled out to obtain3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-1'-trans-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound A) (14 mg, Yield: 100%) as a colorless caramel.

IR (neat): 3350, 1720, 1090, 970 cm⁻¹.

NMR δ(CDCl₃) 6.34 (d, J=16Hz, 1/3H), 6.00 (d, J=11Hz, 2/3H), 5.65 (m,3H), 5.45 (m, 1H), 3.10 (m, 1H).

EXAMPLE 6 ##STR11##

3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound B') (50 mg, 0.14 mmol) was dissolved inmethanol (1.1 ml). To the solution was added a 10% aqueous sodiumhydroxide solution (1.1 ml) at 0° C. After stirring at 0° C. for 18hours, the mixture was neutralized with a 10% aqueous hydrochloric acidsolution while cooling. Under reduced pressure, methanol was distilledout and, after pH was adjusted to 3-4, the resultant mixture wasextracted with ethyl acetate. The extract was dried with anhydrousmagnesium sulfate and then the solvent was distilled out to obtain3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound B) (43 mg,Yield: 89%) as a colorless caramel.

IR (neat): 3350, 1715, 1085, 970 cm⁻¹.

NMR δ(CDCl₃): 6.32 (d, J=16Hz, 1/3H), 6.04 (d, J=12Hz, 2/3H), 5.64 (m,3H), 5.44 (m, 1H), 3.10 (m, 1H).

EXAMPLE 7 ##STR12##

3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound C') (54 mg, 0.145 mmol) was dissolved in methanol (1.16 ml).To the solution was added a 10% aqueous sodium hydroxide solution (1.16ml) at 0° C. After stirring at 0° C. for 8 hours, the mixture wasdiluted with ether and then neutralized with a 10% aqueous hydrochloricacid solution while cooling. Under reduced pressure, methanol wasdistilled out and, after pH was adjusted to 3-4, the resultant mixturewas extracted with ethyl acetate. The extract was dried with anhydrousmagnesium sulfate and then the solvent was distilled out to obtain3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound C) (50 mg, Yield: 96%) as a colorless caramel.

IR (neat): 3350, 2950, 1715 cm⁻¹.

NMR δ(CDCl₃): 6.32 (d, J=16Hz, 1/3H), 6.04 (d, J=11Hz, 2/3H), 5.20-5.90(m, 4H), 1.81 (t, J=2Hz, 3H), 1.00 (m, 3H).

EXAMPLE 8 ##STR13##

3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decen-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound D') (40 mg, 0.086 mmol) was dissolved in methanol (0.69 ml).To the solution was added a 10% aqueous sodium hydroxide solution (0.69ml) at 0° C. After stirring at 0° C. for 8 hours, the mixture wasdiluted with ether and then neutralized with a 10% aqueous hydrochloricacid solution while cooling. Under reduced pressure, methanol wasdistilled out and, after pH was adjusted to 3-4, the resultant mixturewas extracted with ethyl acetate. The extract was dried with anhydrousmagnesium sulfate and then the solvent was distilled out to obtain3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decen-8'-enyl)-7(R)-hydroxy(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound D) (37 mg, Yield: 95%).

IR (neat): 3350, 2950, 1715 cm⁻¹.

NMR δ(CDCl₃): 6.30 (d, J=16Hz, 1/3H), 6.02 (d, J=11Hz, 2/3H), 5.28-5.75(m, 4H), 5.12 (t, J=7Hz, 1H), 1.61 (s, 3H), 1.68 (s, 3H), 0.93 (d,J=6Hz, 3H).

EXAMPLE 9 ##STR14##

Under argon gas atmosphere, 216 mg (9.0 mmol) of sodium hydride wassuspended in 10 ml of dimethyl sulfoxide and stirred at 50° C. for 30minutes to prepare a solution, followed by cooling to 20° C. To thissolution was added dropwise a solution of 4.11 g (9.0 mmol) of(3-ethoxycarbonyl)propyltriphenylphosphonium bromide in dimethylsulfoxide (7 ml). After stirring for 30 minutes, a solution of 1.14 g(3.0 mmol) of3-formyl-6(R)-tertbutyldimethylsiloxy-7(R)-tetrahydropyranyloxy-bicyclo[3.3.0]oct-2-ene(1) in dimethyl sulfoxide (10 ml) was added, followed by stirring atroom temperature for one hour. The reaction mixture was poured intowater, extracted with ether, dried over MgSO₄, and concentrated underreduced pressure to obtain a crude product. This was purified by columnchromatography (ethyl ether/hexane =3/2) to obtain 1.37 g of3-(4'-ethoxycarbonyl-1'-butenyl)-6(R)-tert-butyldimethylsiloxy-7(R)-tetrahydropyranyloxy-bicyclo[3.3.0]oct-2-ene(Compound 2). Yield: 97%.

IR (neat): 1735, 1135, 1020, 835 cm⁻¹.

NMR δ(CDCl₃): 5.90 (d, J=11Hz, 0.9H), 5.4-5.6 (m, 1H), 4.9-5.4 (m, 1H),4.4-4.7 (m, 1H), 4.05 (q, J=7Hz, 2H), 1.20 (t, J=7Hz, 3H), 0.89 (s, 9H),0.05 (s, 6H).

EXAMPLE 10 ##STR15##

To a solution of 1.30 g (2.7 mmol) of the Compound (2) dissolved in 30ml of tetrahydrofuran was added under room temperature 4 ml (40 mmol) ofa tetrahydrofuran solution of tetrabutylammonium fluoride (1M). Afterstirring at room temperature for 5 hours and at 0° C. overnight, thereaction mixture was poured into an aqueous NaHCO₃ solution, followed byextreffect with ethyl ether. The extract was dried over MgSO₄,concentrated under reduced pressure, and the crude product obtained waspurified by column chromatography (ethyl ether/hexan=2/1) to obtain 936mg of3-(4'-ethoxycarbonyl-1'-butenyl)-6(R)-hydroxy-7(R)-tetrapyranyloxybicyclo[3.3.0]oct-2-ene(Compound 3). Yield: 95%.

IR (neat): 3450, 1730, 1370, 1350, 810 cm⁻¹.

NMR δ(CDCl₃) 5.83 (d, J=11Hz, 0.9H), 5.5 - 5.7 (m, 1H), 5.0-5.5 (m, 1H),4.11 (q, J=7Hz, 2H), 1.28 (t, J=7Hz, 3H).

EXAMPLE 11 ##STR16##

Under argon gas atmosphere, 60 mg (0.16 mmol) of the alcohol derivative(3) was dissolved in 0.8 ml of triethylamine and 0.5 ml of dimethylsulfoxide and to the resultant solution was added dropwise a solution of534 mg of SO₃ - pyridine complex in dimethyl sulfoxide (2 ml). Afterstirring for 30 minutes, the reaction mixture was poured into ice-coldwater, extracted with ethyl ether, dried over MgSO₄ and concentrate toobtain a crude aldehyde (4).

Under argon gas atmosphere 13 mg (60%, 0.32 mmol) of sodium hydride wassuspended in tetrahydrofuran and a solution of 82 mg (0.35 mmol) ofdimethyl(2-cyclohexyl-2-oxoethyl)phosphonate was added under roomtemperature. After stirring for 30 minutes, a solution of the abovecrude aldehyde (4) in tetrahydrofuran (2 ml) was added, followed furtherby stirring for one hour. The reaction mixture was poured into ice-coldwater, extracted with ethyl ether, dried over MgSO₄ and the solvent wasevaporated to give a crude product. This was purified by thin layerchromatography (hexane/ethyl ether=1/1) to obtain 66 mg of anα,β-unsaturated carbonyl compound (Compound 5). Yield: 86%.

IR (neat): 1735, 1680, 1665, 1625 cm⁻¹.

NMR δ(CDCL₃): 6.0-7.1 (m, 2H), 5.81 (d, J=11Hz, 0.9H), 5.5-5.7 (m, 1H),5.0-5.5 (m, 1H), 4.4-4.7 (m, 1H), 4.08 (q, J=7Hz, 2H), 1.25 (t, J=7Hz,3H).

EXAMPLE 12 ##STR17##

According to the same procedure as in Example 11, the followingcompounds were synthesized. In Table 1, yields and spectra data areshown.

                  TABLE 1                                                         ______________________________________                                                      Yield   Spectrum                                                A             (%)     data                                                    ______________________________________                                         ##STR18##    35      IR (neat): 1730, 1688, 1668, 1625 cm.sup.-1. NMR                              δ (CDCl.sub.3): 5.9-7.1 (m, 2H), 5.88 (d,                               J=11Hz, 0.9H), 5.0-5.7 (m, 2H), 4.4-4.7 (m, 1H),                              4.08 (q, J=7Hz, 2H), 0.9-1.4 (m, 9H).                    ##STR19##    73      IR (neat): 1730, 1675, 1615 cm.sup.-1. NMR δ                            (CDCl.sub.3): 5.9-6.8 (m, 2H), 5.88 (d, J=11Hz,                               0.9H), 5.0-5.7 (m, 2H), 4.4-4.7 (m, 1H), 4.05 (q,                             J=7Hz, 2H), 0.9-1.4 (m, 9H).                             ##STR20##    100     IR (neat): 1735, 1690, 1683, 1622 cm.sup.-1. NMR                              δ (CDCl.sub.3): 6.0- 7.1 (m, 2H), 5.82 (d,                              J=11Hz, 0.9H), 5.5-5.7 (m, 1H), 5.0-5.5 (m, 1H),                              4.4- 4.7 (m, 1H), 4.04 (q, J= 7Hz, 2H), 0.8-1.5 (m,                           H).                                                      ##STR21##    79      IR (neat): 1730, 1670, 1620 cm.sup.-1. NMR δ                            (CDCl.sub.3): 7.20 (s, 5H), 6.0-6.9 (m, 2H), 5.95                             (d, J=11Hz, 0.9H), 5.0-5.7 (m, 2H), 4.4- 4.7 (m,                              1H), 4.10 (q, J=7Hz, 2H), 1.25 (t, J= 7Hz, 3H).          ##STR22##    100     IR (neat): 1730, 1690, 1685, 1625 cm.sup.-1. NMR                              δ (CDCl.sub.3): 5.9-6.9 (m, 2H), 5.96 (d,                               J=11Hz, 0.9H), 5.0-5.7 (m, 2H), 4.4-4.7 (m, 1H),                              4.1 (q, J=7Hz, 2H), 1.3 (s, 6H).                         ##STR23##    73      IR (neat): 1735, 1690, 1665, 1625 cm.sup.-1.  NMR                             δ (CDCl.sub.3): 5.95-6.8 (m, 2H), 5.85 (d,                              J=11Hz, 0.9H), 5.0-5.7 (m, 2H), 4.4-4.7 (m, 1H),                              4.05 (q, J=7Hz, 2H).                                     ##STR24##    86      IR (neat): 1735, 1692, 1665, 1623 cm.sup.-1. NMR                              δ (CDCl.sub.3): 6.0-7.0 (m, 2H), 5.88 (d,                               J=11Hz, 0.9H), 5.0-5.7 (m, 2H), 4.4-4.7 (m, 1H),                              4.05 (q, J=7Hz, 2H).                                     ##STR25##    88      IR (neat): 2950, 1730, 1688, 1664, 1624 cm.sup.-1.                            Mass m/z; 388, 370, 327, 257, 211, 169, 85,             ______________________________________                                                              43.                                                 

EXAMPLE 13 ##STR26##

To a solution of 60 mg (0.13 mmol) of the α,β-unsaturated ketone(Compound 5) dissolved in 5 ml of methanol, a solution of 6.0 mg ofsodium borohydride in methanol (1 ml) was added at -78° C. After onehour, the reaction mixture was elevated in temperature to -20° C., atwhich the mixture was further stirred for one hour. The reaction wasstopped by addition of acetone, and the reaction mixture was poured intoaqueous saturated ammonium chloride, extracted with ethyl ether andconcentrated under reduced pressure to give a crude alcohol (6). Thecrude alcohol was dissolved in aqueous 65% acetic acid and the solutionwas stirred under heating at 50° C. for 2 hours. After cooling of thereaction mixture, it was poured into an aqueous NaHCO₃ solution,extracted with ethyl acetate, dried over MgSO₄, followed by evaporationof the solvent, to give a crude product. This was purified by thin layerchromatography to obtain 29 mg of a 15α-diol derivative (E') as highpolar component.

IR (neat): 3450, 1730 cm⁻¹.

NMR δ(CDCl₃): 5.90 (d, J=11Hz, 0.9H), 4.9-5.8 (m, 4H), 4 5-4.8 (m, 1H),4.07 (q, J=7Hz, 2H), 1.25 (t, J=7Hz, 3H).

EXAMPLE 14

According to the same procedure as in Example 13, the followingcompounds were synthesized. In Table 2, yields and spectra data areshown. ##STR27##

                  TABLE 2                                                         ______________________________________                                        Com-                Yield   Spectrum                                          pound A             (%)     data                                              ______________________________________                                        F'                                                                                                54      IR (neat): 3360, 1730 cm.sup.-1. Mass m/z:                                    400, 382, 271, 234, 117, 81.                      G'                                                                                   ##STR28##    23      IR (neat): 3350, 1735 cm.sup.-1. NMR δ                                  (CDCl.sub.3): 5.91 (d, J=11Hz, 0.9H), 5.0-5.7                                 m, 4H), 4.07 (q, J=7Hz, 2H), 1.23 (t, J=7Hz,                                  3H).                                              H'                                                                                   ##STR29##    48      IR (neat): 3380, 1735 cm.sup.-1. NMR δ                                  (CDCl.sub.3): 5.89 (d, J=11Hz, 0.9H), 5.0-5.6                                 m, 4H), 4.05 (q, J=7Hz, 2H), 0.7-1.0 (m,                                      9H).                                              I'                                                                                   ##STR30##    33      IR (neat): 3360, 1730 cm.sup.-1. NMR δ                                  (CDCl.sub.3): 7.16 (s, 5H), 5.92 (d, J=11Hz,                                  0.9H), 5.0-5.7 (m, 4H), 4.04 (q, J=7Hz, 2H),                                  1.20 (t, J=7Hz, 3H).                              J'                                                                                   ##STR31##    52      IR (neat): 3400, 1730 cm.sup.-1. Mass m/z:                                    386, 368, 311, 287, 192, 143, 91.                 K'                                                                                   ##STR32##    46      IR (neat): 3350, 1735 cm.sup.-1. Mass m/z:                                    386, 368, 283, 192, 131, 91.                      L'                                                                                   ##STR33##    39      IR (neat): 3370, 1735 cm.sup.-1. Mass m/z:                                    398, 380, 315, 297, 192, 81.                      M'                                                                                   ##STR34##    47      IR (neat): 3350, 2960, 2925, 2870, 1735,                                      1155, 970 cm.sup.-1. NMR δ                                              (CDCl.sub.3): 6.27 (d, J=15Hz, 0.1H), 5.99                                    (d, J=11Hz, 0.9H), 5.3-5.7 (m, 4H), 4.16 (m,                                  1H), 4.13 (q, J=7.3Hz, 2H), 3.8 (m, 1H), 3.08                                 (m, 1H). Mass m/z: 372, 354,                      ______________________________________                                                                    328, 234.                                     

EXAMPLE 15 ##STR35##

To a solution of 29 mg (0.075 mmol) of the 15α-diol derivative (CompoundE') dissolved in 2 ml of ethanol, 1 ml of an aqueous 5% sodium hydroxidesolution was added under room temperature, followed by stirring for onehour. After completion of the reaction, the reaction mixture wascarefully neutralized with a 5N hydrochloric acid finally to pH 4 to 3.This was extracted with ethyl acetate, dried over MgSO₄ and the solventevaporated to give a crude product. This was purified through a neutralsilica gel capillary column to obtain 23 mg of a carboxylic acid (E).Yield: 85%.

IR (neat): 3350, 1700 cm⁻¹.

NMR δ(CDCl₃): 6.29 (d, J=15Hz, 0.1H), 6.10 (d, J=11Hz, 0.9H), 5.4-5.7(m, 3H), 5.3-5.4 (m, 1H), 3.7-3.9 (m, 2H), 3.0-3.2 (m, 1H). Mass m/z:342, 324.

EXAMPLE 16

According to the same procedure as in Example 15, the followingcompounds were synthesized. In Table 3, yields and spectra data areshown. ##STR36##

                  TABLE 3                                                         ______________________________________                                        Com-                Yield   Spectrum                                          pound A             (%)     data                                              ______________________________________                                                            52      NMR δ (CDCl.sub.3): 6.28 (d, J=15Hz,                                    0.1H), 6.01 (d, J=11Hz, 0.9H), 5.2-5.7 (m,                                    4H), 3.7-4.2 (m, 2H), 3.1 (m, 1H), 0.9- 3.0                                   (m, 23H). Mass m/z: 354, 336, 259, 177, 91,                                   81.                                               G                                                                                    ##STR37##    59      IR (neat): 3320, 1700 cm.sup.-1. NMR δ                                  (DMSO-d.sub.6): 6.23 (d, J=15Hz, 0.1H), 5.97                                  (d, J=11Hz, 0.9H), 5.2-5.7 (m, 4H), 3.9-4.2                                   (m, 1H), 0.9-1.2 (m, 6H).                         H                                                                                    ##STR38##    96      IR (neat): 3350, 1705 cm.sup.-1. NMR δ                                  (CDCl.sub.3): 6.28 (d, J= 15Hz, 0.1H), 6.01                                   (d, J=11Hz, 0.9H), 5.4-5.7 (m, 3H), 3.9-4.1                                   (m, 1H), 3.7-0.9 (m, 1H), 0.8-1.0 (m, 6H).                                    Mass m/z: 358, 340.                               I                                                                                    ##STR39##    89      IR (neat): 3340, 1700 cm.sup.-1. NMR δ                                  (CDCl.sub.3): 7.1-7.5 (m, 5H), 6.29 (d,                                       J=15Hz, 0.1H), 6.01 (d, J=11Hz, 0.9H),                                        5.5-5.8 (m, 3H), 5.3-5.5 (m, 1H), 4.1- 4.2                                    (m, 1H), 3.7-3.9 (m, 1H). Mass m/z: 364,                                      346.                                              J                                                                                    ##STR40##    52      NMR δ (CDCl.sub.3): 6.28 (d, J=15Hz,                                    0.1H), 6.01 (d, J=11Hz, 0.9H), 5.3-5.8 (m,                                    4H), 3.83 (m, 2H), 3.10 (m, 1H), 1.1-2.8 (m,                                  20H), 0.89 (s, 3H), 0.85 (s, 3H). Mass m/z:                                   358, 340, 314, 259, 206, 164, 95, 57.             K                                                                                    ##STR41##    63      NMR δ  (CDCl.sub.3): 6.28 (d, J=15Hz,                                   0.1H), 6.01 (d, J=11Hz, 0.9H), 5.3-5.7 (m,                                    4H), 4.19 (m, 1H), 3.78 (m, 1H), 1.0-3.2 (m,                                  25H), 0.89-0.93 (two d, 3H). Mass m/z: 358,                                   340, 314, 259, 206, 164, 117, 57.                 L                                                                                    ##STR42##    91      NMR δ (CDCl.sub.3): 6.28 (d, J=15Hz,                                    0.1H), 6.01 (d, J=11Hz, 0.9H), 5.2-5.7 (m,                                    4H), 4.05 (m, 1H), 3.80 (m, 1H), 0.8-3.5 (m,                                  25H), 0.76 (d, J=7.3 Hz, 3H). Mass m/z: 370,                                  352, 326, 259, 206, 164, 81, 55.                  M                                                                                    ##STR43##    73      IR (neat): 3350, 2950, 2860, 1700 cm.sup.-1.                                  NMR δ (CDCl.sub.3): 6.28 (d, J=15Hz,                                    0.1H), 6.00 (d, J=11Hz, 0.9H), 5.2-5.7 (m,                                    4H), 4.20 (m, 1H), 3.80 (dd, J=16, 9.5Hz,                                     1H), 3.06 (m, 1H). Mass m/z: 344, 326, 300,                                   177.                                              ______________________________________                                    

(Preparation of pharmaceutical) EXAMPLE 17

5 mg of3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound A') dissolved in 5 ml of ethanol, 0.2 g of carboxymethylcellulose calcium, 20 mg of silicon dioxide, 0.2 g of magnesium stearateand 5 g of mannitol were mixed and dried according to a conventionalmethod. The mixture was made up to 10 g with addition of mannitol andthen mixed sufficiently until it became uniform. The resultant mixturewas directly punched by use of a mortar and a pounder according to aconventional manner to obtain 100 tablets containing 50 μg of the activesubstance in one tablet.

EXAMPLE 18

70 mg of β-cyclodextrin inclusion compound (content of Compound B': 5mg) included therein3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyltrans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound B'), 0.2 g of carboxymethyl cellulose calcium, 20 mg ofsilicon dioxide, 0.2 g of magnesium stearate and dried mannitol weremixed such that the mixture was made up to 10 g and then mixedsufficiently until it became uniform. The resultant mixture was directlypunched by use of a mortar and a pounder according to a conventionalmanner to obtain 100 tablets containing 50 μg of the active substance inone tablet.

EXAMPLE 19

The same procedures were carried out as in Example 1 except that 10 mgof3-(4'-methoxycarbonyl-1'-butenyl)6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound C') was employed as a starting material to obtain 100 tabletscontaining 100 μg of the active substance in one tablet.

EXAMPLE 20

70 mg of β-cyclodextrin inclusion compound (content of Compound D': 5mg) included therein3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decen-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound D'), 0.23 g ofmagnesium stearate and lactose were mixed such that the mixture was madeup to 2.3 g and then mixed sufficiently until it became uniform. Theresultant mixture was charged into a gelatin capsule No. 3 according toa conventional method to obtain 100 capsules wherein 50 μg of an activesubstance was contained in each capsule.

EXAMPLE 21

14 mg of β-cyclodextrin inclusion compound (content of Compound C': 1mg) included therein3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound C'), was dissolved in 100 ml of a distilled water. Theresultant solution was sterilized according to a conventional manner andaliquots each of 1 ml were injected into ampoules of 5 ml capacity toobtain 100 injection preparations containing 10 μg of the activesubstance in one injection.

EXAMPLE 22

A solution of 5 mg of3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclohexyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene (Compound E) dissolved in 5 ml of ethanol, 0.2 g ofcarboxymethyl cellulose calcium, 20 mg of silicon dioxide, 0.2 g ofmagnesium stearate and 5 g of mannitol were mixed in a conventionalmanner and dried. Then, mannitol was added to a total weight of 10 g,followed by thorough mixing until homogeneous, and the resultant mixturewas tabletted directly by means of a mortar and a pestle to obtain 100tablets containing 50 μg of the active substance in one tablet.

EXAMPLE 23

For Compound E', Compound F, Compound F,, Compound G, Compound G',Compound H, Compound H', Compound I, Compound I', Compound J, CompoundJ', Compound K, Compound K', Compound L, Compound L', Compound M andCompound M', according to the same procedure as in Example 22, 100tablets containing 50 μg of the active substance in one tablet wereobtained.

EXAMPLE 24

A blend of 70 mg [content of Compound E': 5 mg] of α-cyclodextrininclusion compound of3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclohexyl-trans-1'-propenyl)-7(R)-hyroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound E'), 0.2 g of carboxymethyl cellulose calcium, 20 mg ofsilicon dioxide, 0.2 g of magnesium stearate and the balance of mannitoladded to make up 10 g was thoroughly mixed until homogeneous, andtabletted directly in a conventional manner to obtain 100 tabletscontaining 50 ug of the active substance in one tablet.

EXAMPLE 25

A blend of 70 mg [content of Compound F: 5 mg] of β-cyclodextrininclusion compound of3-(4'-carboxy-1-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-nonen-6'-ynyl)-7(R)-hyroxy-(1S,5S)-cis-bicyclo[3.3.0]oct2-ene(Compound F), 0.23 g of magnesium stearate and the balance of lactoseadded to make up 23 g, was thoroughly mixed until homogeneous and filledin No. 3 gelatin capsules in a conventional manner to obtain 100capsules containing 50 μg of the active substance in on capsule.

EXAMPLE 26

A solution of 14 mg [content of Compound G': 1 mg] of β-cyclodextrininclusion compound of3'-(4'-ethoxy-carbonyl-1'-butenyl)-6(S)-(3'-(S)-hydroxy-5'(RS)-methyltrans-1'-nonen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene(Compound G') dissolved in 100 ml of distilled water was sterilized in aconventional manner, and aliquots each of 1 ml were injected intoampoules of 5 ml capacity to obtain 100 injection preparationscontaining 10 μg of the active substance in one ampoule.

EXPERIMENT 1 Vasodilative effect (Method)

Female and male adult dogs were anesthetized by intraveneousadministeration of 30 mg/kg of sodium pentobarbital and fixed on theirback positions. The right femoral artery was perfused at constant flowwith the dog's own blood by means of a peristaltic pump (Harvard Co.).The perfusion pressure was measured with an electromanometer andsystemic blood pressure was measured in the other femoral artery with apressure transducer. As an anticoagulant, 500 U/kg of heparin sodium wasintravenously administered.

The compound of the present invention was dissolved in 10 % ethanol -90% physiological salt solution and administered into arterial bloodthrough a thick rubber tube provided in the perfusion circuit. Thevasodilative effect of the compound of the present invention isexpressed by the change ratio of perfusion pressure after administrationinto the artery. The results are shown in the following Table.

                  TABLE 4                                                         ______________________________________                                                  Administration                                                                            Dose     Perfusion pres-                                Compound No.                                                                            route       (μg/kg)                                                                             sure change (%)                                ______________________________________                                        Compound A                                                                              intraarterial                                                                             100      -18                                            Compound B                                                                              intraarterial                                                                             100      -12                                            Compound C                                                                              intraarterial                                                                             100      -23                                            Compound D                                                                              intraarterial                                                                             100      -28                                            OP-41483  intraarterial                                                                             100      -16                                            ______________________________________                                    

EXPERIMENT 2 Hypotensive effect (Method)

Male wistar strain rats (weighing 240-290 g) were anesthetized byintraperitoneal administration of 50 mg/kg of sodium pentobarbital, andblood pressures were measured. The compound of the present invention wasadministered intravenously as a solution dissolved in 10% ethanol - 90%physiological salt solution. The hypotensive effect is expressed by thepercent change of average blood pressure after intravenousadministration (relative to that before administration). The results areshown in the following Table 5.

                  TABLE 5                                                         ______________________________________                                        Hypotensive effect in anesthetited rats                                                  Administration                                                                             Dose      Percent                                     Compound No.                                                                             route        (μg/kg)                                                                              change (%)                                  ______________________________________                                        Compound A intravenous  3         -43                                         Compound B intravenous  1         -34                                         Compound C intravenous  0.3       -40                                         Compound D intravenous  3         -38                                         OP-41483   intravenous  10        -39                                         ______________________________________                                    

EXPERIMENT 3 Platelet aggregation inhibiting effect (Method)

Bloods were sampled from healthy volunteers (22-34 years old) with noadministration of drug for 2 weeks or more early in the morning whenthey were hungry. By use of an injector filled with 5 ml of 3.8% sodiumcitrate solution, 50 ml of blood was sampled, immediately stirred byturning upside down and centrifuged at 200xg for 15 minutes. Thesupernatant was separated as the PRP (platelet rich plasma) and theresidue further subjected to centrigugation at 2000xg for 15 minutes,followed by recovery of the supernatant as PPP (poor platelet plasma)which was provided for use in the experiment.

PRP (250 μl) was placed in a cuvette, 5 μl of an 1% ethanol solution ofthe compound of the present invention or an 1% ethanol solution wasadded, and incubation was carried out at 37° C. for one minute. Then, anaggregation inducing agent (ADP) was added and the process ofaggregation was recorded by Aggregometer (Sienco Co.).

As the concentration of ADP, the minimum concentration of ADP (2-10 μM)to give the maximum aggregation for respective platelets were employed.The inhibition percentage of platelet aggregation was calculated by thefollowing formula:

    Inhibition percentage=(A-B)/A×100

A: Maximum aggregation ratio during addition of solvent (1% ethanolsolution)

B: Maximum aggregation ratio during addition of the compound of thepresent invention.

The platelet aggregation inhibiting effects of the compounds of thepresent invention are shown in terms of IC₅₀ values in Table 6.

                  TABLE 6                                                         ______________________________________                                        Human platelet aggregation inhibiting effect (in vitro)                                     Platelet aggregation                                                          inhibiting ratio                                                Compound No.  (IC.sub.50)                                                     ______________________________________                                        Compound A    1.4 × 10.sup.-8 M                                         Compound B    7 × 10.sup.-9 M                                           Compound C    .sup. 8 × 10.sup.-10 M                                    Compound D    2 × 10.sup.-8 M                                           Compound E    5 × 10.sup.-9 M                                           Compound F    4 × 10.sup.-9 M                                           Compound G    .sup. 6 × 10.sup.-10 M                                    Compound H    8 × 10.sup.-9 M                                           Compound I    8 × 10.sup.-8 M                                           Compound J    2 × 10.sup.-7 M                                           Compound K    2 × 10.sup.-9 M                                           Compound L    3 × 10.sup.-7 M                                           Compound M    4 × 10.sup.-9 M                                           OP-41483      9 × 10.sup.-9 M                                           ______________________________________                                    

EXPERIMENT 4 Antiulcer effect (1) (Method)

Male SD-strain rats (weighing 220-255 g) were fasted for 20 hours (waterwas given ad libitum) and, after further abstinence from food and waterfor 4 hours, the compound of the present invention was administeredorally, followed further by oral administration of 1 ml of 0.6 Nhydrochloric acid 30 minutes later. One hour after administration ofhydrochloric acid, the stomach was enucleated under chloroformanesthesia. The fluid in the stomach was discharged and 7.5 ml of a 1%formalin solution was injected into the stomach to fix the gastricmucosa. Then, the stomach was dissected along the greater curvature andthe length of the gastric mucosa damage was measured under a steroscopicmicroscope. The compound of the present invention was dissolved in 5%ethanol - 95% physiological salt solution and administered at a dose of25 μg/kg in a volume of 5 ml/kg.

The antiulcer effect of the compound of the present invention wascalculated by the following formula: ##EQU1## l: length of gastricmucosa damage in the group to which the compound of the presentinvention is administered;

lo: length of gastric mucosa damage in the group of non-administrationof drug.

The results are shown in the following Table 7.

                  TABLE 4                                                         ______________________________________                                        Antiulcer effect                                                                                              Inhibition of                                           Administration                                                                             Dose     gastric mocosa                                Compound No.                                                                            route        (μg/kg)                                                                             damage (%)                                    ______________________________________                                        Compound C                                                                              Oral         25       95.5                                          Compound D                                                                              Oral         25       91.5                                          PGE.sub.2 Oral         25       61.1                                          OP-41483  Oral         25       -28.3                                                                         (worsened)                                    ______________________________________                                    

EXPERIMENT 5 Antiulcer effect (2) (Method)

Male wistar strain rats (weighing 250-280 g) were fasted for 18 hourssubjected to peritoneotomy under ether anesthesia for ligature ofpylorus, and after 4 hours under abstinence from food and water, gastricjuice was sampled. The gastric juice was centrifuged at 3000 rpm for 10minutes, and then the amount, pH and acidity of the gastric juice weremeasured. The acidity was measured by titration by means of an automatictitrating device (Toa Denpa Kogyo) with a 0.1N NaOH to pH 7.0 andcalculating according to the following formula: ##EQU2## The gastricjuice secretion inhibition percentage was calculated according to thefollowing formula: ##EQU3## A: Amount of gastric acid excreted inControl group B: Amount of gasatric acid excreted in Drug group

The drugs to be tested were administered subcutaneously immediatelyafter pylorus ligature. The results are shown in Table 8.

                  TABLE 8                                                         ______________________________________                                        Rat gastric acid inhibiting effect                                                                 Amount of                                                                     gastric acid                                                        Dose      secreted                                                 Compound No.                                                                             (μg/kg)                                                                              (mEq/l)    Inhibition (%)                                ______________________________________                                        Solvent    --        73.6       --                                            Compound E 100       28.7       61.0                                          Compound F 100       13.4       81.8                                          Compound G 100       25.3       65.6                                          Compound H 100        7.4       89.9                                          Compound I 100       19.5       73.5                                          Compound J 100       60.3       18.1                                          Compound K 100       21.7       70.5                                          Compound L 100       46.5       36.8                                          Compound M 100       19.5       73.5                                          ______________________________________                                    

We claim:
 1. A prostaglandin I₂ analogue for circulation ameliorationhaving the following formula: ##STR44## wherein R represents a hydrogenatom, a methyl group or an ethyl group.
 2. The prostaglandin I₂ analogueaccording to claim 1, wherein R is a hydrogen atom.
 3. The prostaglandinI₂ analogue according to claim 1, wherein R is a methyl group.
 4. Theprostaglandin I₂ analogue according to claim 1, wherein R is an ethylgroup.